Grant: Operating Grant

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to be one of the leading causes of death due to an infectious disease globally, with an estimated 8.8 million new cases and 1.45 million deaths in 2010. In the majority of individuals infected with Mtb, the bacteria establish a latent, asymptomatic infection that can persist for decades. About 5-10% of latently infected individuals will develop active disease in their lifetime and host immunosuppression (HIV coinfection) markedly increases the risk of reactivation. As much as one-third of the world's population is latently infected, representing a large reservoir for potential reactivation and subsequent spread. Latent TB infection presents major challenges to effective control of TB since currently available drugs cannot kill latent organisms. Mtb persisters, which are characterized by reduced or altered metabolic activity and enhanced drug tolerance, are a major contributor of latent infection. However, the origin of Mtb persisters and the mechanism of drug tolerance remain poorly understood. The goal of my project is to elucidate molecular mechanisms underlying Mtb persistence and drug tolerance. My laboratory has recently identified Lsr2 as a global regulator of Mtb. Our preliminary data suggest Mtb employs Lsr2 as a key molecular switch in the formation of persisters. In this application, I designed a number of experiments to address the central role of Lsr2 in Mtb persistence and drug tolerance. Our studies will help to elucidate the genetic and metabolic pathways involved in Mtb persistence and identify potentially new therapeutic and diagnosis targets of latent TB infection.